The human blood-forming (hematopoietic) system is comprised of a variety of white blood cells (including neutrophils, macrophages, basophils, mast cells, eosinophils, T and B cells), red blood cells (erythrocytes) and clot-forming cells (megakaryocytes, platelets).
It is understood that certain hematopoietic growth factors such as chemicals and proteins naturally occurring inside animals are responsible for the differentiation of a small number of “stem cells” into a variety of blood cell progenitors for the tremendous proliferation of those cells, and for the ultimate differentiation of mature blood cells from those lines. The hematopoietic regenerative system functions well under normal conditions. However, when stressed by chemotherapy, radiation, or natural myelodysplastic disorders, a resulting period during which patients are seriously leukopenic, anemic, or thrombocytopenic occurs. Neutropenia is an abnormally low level of neutrophils in the blood. Neutrophils are white blood cells (WBCs) produced in the bone marrow and comprise approximately 60% of the blood. These cells are critically important to an immune response and migrate from the blood to tissues during an infection. They ingest and destroy particles and germs. Germs are microorganisms such as bacteria, protozoa, viruses, and fungus that cause diseases. Neutropenia is an especially serious disorder for cancer patients who may have reduced immune functions because it makes the body vulnerable to viral, bacterial and fungal infections. White blood cells are especially sensitive to chemotherapy. The number of cells killed during radiation therapy and chemotherapy depends upon the dose and frequency of the treatment.
Neutropenia is a blood disorder wherein the number of neutrophils in the blood is abnormally low as assessed by an Absolute Neutrophil Count (ANC). A neutrophil shortage corresponds to an increased risk of microbial infection. The blood of healthy human adults contains about 2500 to 6000 neutrophils per mm3. In children under the age of six, the count may be lower. Various sources have set the threshold for the diagnosis of neutropenia at different measured neutrophil levels ranging from an ANC of about 2000 neutrophils per mm3 to about 1500 neutrophils per mm3. See The Merck Manual 18th Ed. 2006, Section 11, the entire disclosures of which are incorporated herein by reference. Severe neutropenia is diagnosed when the ANC falls below 500 neutrophils per mm3. The symptoms, of increased risk of infection depend on the severity of the neutropenia and on the duration of the disorder.
Neutropenia treatable by compounds and methods of the present invention may be a chronic disorder. Neutropenia as a chronic disorder may be further classified as congenital, cyclical and idiopathic neutropenia. Chronic congenital neutropenia is inherited by a small number of individuals. The most severe form of congenital neutropenia is Kostmann's Syndrome and there are other, milder variations. Symptoms include frequent infections and fevers.
Cyclical neutropenia results from a regulatory defect at the hematopoietic stem cell level that causes oscillations in production of neutrophils as well as other types of blood cells. Individuals with this disorder will have neutrophil counts of about 100 neutrophils per mm3 for three to six days out of every cycle. The neutrophil count ranges from severe to moderate neutropenia levels through most of the cycle.
Chronic idiopathic neutropenia refers to severe chronic neutropenia that does not clearly fall into either of the above classifications. Individuals suffering from chronic idiopathic neutropenia typically acquire the disorder after having normal neutrophil counts earlier in life. It is estimated that neutropenia may occur as a congenital or idiopathic disorder in an estimated frequency of one per 200,000 in the population.
Neutropenia may also be occurred secondary to another condition such as cancer or Acquired Immunodeficiency Syndrome (AIDS). Neutropenia may also be occurred secondary to an event such as a drug therapy. Thus, neutropenia may result from physiological disorders that directly affect the immune system. For example, diminished neutrophil production will be resulted when leukemia, myeloma, lymphoma or a metastatic solid tumor such as, for example, breast or prostate cancer, infiltrate and replace bone marrow. Transient neutropenia is often associated with viral infections. Chronic neutropenia is often associated with immunodeficiency resulting from a viral infection, for example, AIDS resulting from infection with Human Immunodeficiency Virus (HIV). Autoimmune neutropenia may be associated with circulating antineutrophil antibodies.
A much more common cause is neutropenia as a side effect of drug therapy, particularly cancer chemotherapy, radiation therapy for cancer and bone marrow transplantation associated with cancer therapy. Neutropenia secondary to drug therapy can thus be subdivided into two groups. The first involves immune-mediated neutropenia that may arise from drugs that act as haptens to stimulate antibody formation. Acute hypersensitivity reactions such as those caused by diphenylhydantoin and phenobarbital may last a few days. However, chronic hypersensitivity reactions may last for months or years. See The Merck Manual, 18th Ed.
The second area of drug-induced neutropenia involves the severe neutropenia that predictably occurs after large doses of cytoreductive cancer drugs and which also accompanies ionizing radiation therapy. These cytotoxic therapies induce neutropenia because of the proliferative nature of neutrophil precursor cells and the normal rapid turnover rate of circulating neutrophils. See The Merck Manual, 18th Ed. The risk of neutropenia secondary to cancer chemotherapy or radiotherapy depends on the type and stage of the cancer and the type, the dosage and the schedule of cancer treatment. Each year over 1.5 million cancer patients in the US received chemotherapy. About one half of chemotherapy patients develop neutropenia. At present, less than 10% of chemotherapy patients receive prophylactic treatment to prevent neutropenia.
Therapy that exists currently for hematopoietic disorders include the use of proteineous hematopoietic factors such as EPO, G-CSF, GM-CSF, CSF-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IGF-I, or LIF (Leukemic Inhibitory Factor) and other chemicals. Therapy for raising neutrophil levels consists primarily of filgrastim (Nupogen®) and more recently, pegfilgrastim (Neulasta™), a longer acting derivative of filgrastim. Filgrastim is a recombinant version of a human protein, G-CSF (granulocyte-colony stimulating factor), that selectively stimulates the production of white blood cells. G-CSF is currently the drug of choice for neutropenia. Since both of these drugs are recombinant proteins they are not active orally and must be administered by injection. In addition, protein-based drugs are often subject to rapid metabolism.
New agents, in particular, non protein-based drugs are needed which are useful in the treatment of neutropenia. In particular, agents are needed that demonstrate biological activity when administered via routes other than injection. Particularly, agents that may be orally active are needed, as they may serve to enhance patient compliance.
Dithiolopyrrolones are a group of compounds with 1,2-dithiolo[4,3-b]pyrrol-5(4H)-one ring. Compounds bearing this basic structural feature have been known in the art with a broad range of activities, including antimicrobial, chemopreventive (Sharma et al., 1994) and anticancer (WO 99/12543, WO2003/080624, both of Webster et al.). However, the surprising, novel activities of increasing white blood cells in animals was not known until now. Certain synthetic dithiolopyrrolones and their antimicrobial activities have been disclosed (D. S. Bhate & Y. M. Sambray, 1963. Hindustan, Antibiotic Bulletin 6(1): 17-18; Katsuaki Hagio et al. Bull. Chem. Soc. Jpn 1974, 47, 1484-1489; Broom et al. WO 9505384 and Godfrey & Dell, GB2170498, Webster et al. WO 99/12543, WO2003/080624).
The present invention relates to new dithiolopyrrolones, to their novel activities in increasing white blood cells and their use in promoting white blood cells, in preventing and treatment of microbial infections and of blood disorders such as neutropenia.